Abstract
The immune system (IS) and the central nervous system (CNS) are functionally coupled, and a large number of endogenous molecules (i.e., the chemokines for the IS and the classic neurotransmitters for the CNS) are shared in common between the two systems. These interactions are key elements for the elucidation of the pathogenesis of central inflammatory diseases. In recent years, evidence has been provided supporting the role of chemokines as modulators of central neurotransmission. It is the case of the chemokines CCL2 and CXCL12 that control pre- and/or post-synaptically the chemical transmission. This article aims to review the functional cross-talk linking another endogenous pro-inflammatory factor released by glial cells, i.e., the chemokine Regulated upon Activation Normal T-cell Expressed and Secreted (CCL5) and the principal neurotransmitter in CNS (i.e., glutamate) in physiological and pathological conditions. In particular, the review discusses preclinical data concerning the role of CCL5 as a modulator of central glutamatergic transmission in healthy and demyelinating disorders. The CCL5-mediated control of glutamate release at chemical synapses could be relevant either to the onset of psychiatric symptoms that often accompany the development of multiple sclerosis (MS), but also it might indirectly give a rationale for the progression of inflammation and demyelination. The impact of disease-modifying therapies for the cure of MS on the endogenous availability of CCL5 in CNS will be also summarized. We apologize in advance for omission in our coverage of the existing literature.
Highlights
The immune system and the central nervous system (CNS) cross-talk, and this interaction are pivotal to the onset and the progression of central neurodegenerative diseases (i.e., Alzheimer’s disease and amyotrophic lateral sclerosis), as well as in classic autoimmune-inflammatory disorders [i.e., multiple sclerosis (MS)]
Comparable results could be drawn when using antibodies raised against the N-terminal of the CCR1, CCR3, and CCR5 receptor proteins, leading to conclude that (i) the receptor composition of the chemokine oligomers controlling glutamate release in mouse and human cortical nerve endings is largely conserved, (ii) the involvement of CCR3 in the oligomer expression dictates the coupling to inhibitory G proteins bridging negatively the chemokine receptor complex to the adenylyl cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) transducing mechanism (Figure 1; Table 2), and (iii) the mouse brain tissue is appropriate to investigate the effects of CCL5 on central glutamatergic transmission [66]
As to the second messengers, the strict correlation linking CCL5 levels, glutamate release efficiency and IP3, and cAMP accumulation was confirmed by the observation that administration of drugs able to reduce the overexpression of CCL5 in CNS [i.e., the antidepressant desipramine (DMI)] [126] restored both presynaptic functions at glutamatergic nerve endings in the cortex of mice suffering from EAE
Summary
The immune system and the central nervous system (CNS) cross-talk, and this interaction are pivotal to the onset and the progression of central neurodegenerative diseases (i.e., Alzheimer’s disease and amyotrophic lateral sclerosis), as well as in classic autoimmune-inflammatory disorders [i.e., multiple sclerosis (MS)]. The expression and the release of CCL5 from astrocytes is tightly controlled by several receptor subtypes, including opioid receptors [49, 50], group III metabotropic glutamate receptors [2], alpha/beta noradrenergic receptors [51,52,53], and sphingosine-1-phosphate receptor (S1PR) subtype 1 [54], as well as by endogenous neurotoxin such as quinolinic acid acting at NMDA receptors [55] These receptors represent targets of therapeutics for inflammatory autoimmune disease typified by overexpression of CCL5. In physiological conditions, the expression of CCR5 in astrocytes is low but rapidly increases to abnormal pathological levels upon stimulation with TNF-alpha and by IL-1beta released by neighboring microglial cells, which causes persistent adaptation leading to a significant increase in the expression of most of the CCR proteins [55] This cascade of events occurs during inflammation, so that the overexpression of the receptors targeted by CCL5 is an event intimately linked to pathological conditions. The existence of CCR1, CCR3, and CCR5 receptor proteins in neurons was confirmed by other groups [20, 78,79,80,81], despite some discrepancies concerning their exact location
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